Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([O:62][Si](C(C)(C)C)(C)C)[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]>CN(C)C=O>[C:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:71])[C@H:30]([CH3:70])[CH2:31][C@H:32]([OH:62])[C@@H:33]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:34][C@@H:35]([CH:51]([CH3:53])[CH3:52])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:38]=1)(=[O:24])[NH2:23]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCC(N)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
50 mg of tetrabutylammonium fluoride trihydrate are added to 115 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid [N-(3-carbamoyl-propyl)]-amide in 4 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 5 hours at room temperature and then concentrated by evaporation. 20 ml of saturated sodium hydrogen carbonate solution are added to the evaporation residue and the mixture is extracted repeatedly with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and concentrated by evaporation. The residue is purified by means of FC (18 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1): 0.24.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([OH:11])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25].O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([O:11][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)n[nH]1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(OCCOCCOC)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3.4 g 5-Hydroxy-2H-pyrazole-3-carboxylic acid ethyl ester and 3 g K2CO3 in 50 ml acetonitrile, 4 g 1-(2-Bromo-ethoxy)-2-methoxy-ethane were added. After stirring for 1 h at RT the reaction was heated to 50° C. for 4 h. Then 50 ml of water were added and the mixture was extracted with DCM (3×100 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica eluting with a DCM/MeOH gradient. Yield: 1 g.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:16]=[CH:17][C:12]([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[CH:13][CH:14]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CCCCC(CC)COC(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(CC)COC(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
Mix chlorobutyryl chloride (16.9 g) and AlCl3 (29.3 g) at room temperature. Add 2-phenylacetic acid, 2-ethylhexyl ester (27.6 g), keeping the temperature below 10° C. Heat at 35° C. for 24 hours, quench in ice water (200 g). Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Dilute the residue with ethanol (150 mL), add hydrogen chloride (5 g) and heat to 75° C. After 2.5 hours, add another 5 g of hydrogen chloride and stir at 75° C. for 24 hours. Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][NH+:5]=1.[SH:14][C:15]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=2[N:16]=1>C(O)C.O.[OH-].[Na+]>[CH3:11][O:10][C:9]1[C:4]([CH2:3][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:23][C:17]=3[N:16]=2)=[N:5][CH:6]=[CH:7][C:8]=1[O:12][CH3:13]
Reactant: FC(F)C(F)(F)Oc1ccc2[nH]c(S)nc2c1
Reactant: COc1cc[nH+]c(CCl)c1OC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(CSc2nc3cc(OC(F)(F)C(F)F)ccc3[nH]2)c1OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.38 g (1.7 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride is added to a solution of 0.46 g (1.7 mmol) of 2-mercapto-5-(1,1,2,2-tetra fluoroethoxy)-1H-benzimidazole in 10 ml of ethanol, 10 ml of water and 1.8 ml of 2N sodium hydroxide solution; after the mixture has been stirred at 20° C. for one hour, a further 10 ml of water are added dropwise. The mixture is then stirred at 20° C. for a further four hours. The solid which has precipitated out is filtered off, washed with 0.01N sodium hydroxide solution and then with water until neutral and dried to constant weight. 0.63 g (90% of theory) of the title compound is obtained as a colorless crystalline powder of m.p. 98°-102° C.
Reaction SMILES: [ClH:1].[Cl:2][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.Cl.[NH3:15]>CO.CCOCC>[ClH:2].[ClH:1].[NH2:15][CH:3]1[C:12]2[N:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cnc2c(c1)CCCC2Cl
Reactant: N
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cc1cnc2c(c1)CCCC2N

Procedure:
The 8-chloro product of Example 2 (17 g.) was dissolved in methanol saturated with ammonia (400 ml.) and heated at 80° in a stainless steel bomb for 24 hours. The solvnet was removed in vacuo and the residual oil titurated with anhydrous ether (3 × 50 ml.) and the triturates discarded. The oily solid was dissolved in water the pH adjusted to 9.0 with sodium carbonate and extracted with ether (3 × 150 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give a pale yellow oil (5.5 g.). A sample (500 mg) was dissolved in anhydrous ether (25 ml.) and the solution treated with excess ethereal hydrogen chloride and the resultant solid recrystallised from methanol-ether to give 8-amino-3-methyl-5,6,7,8-tetrahydroquinoline dihydrochloride quarter hydrate as colourless needles m.p. 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: COC(C)(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
A solution of 3-methoxy-3-methylbutan-1-ol (2.50 g, 21.16 mmol) in DCM (30 mL) was treated with p-toluene sulfonyl chloride (5.00 g, 26.2 mmol) followed by TEA (4.28 g, 42.3 mmol) and stirred at RT for 3 h. The mixture was washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 3-methoxy-3-methylbutyl 4-methylbenzenesulfonate (2.84 g, 49%). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J=8.2 Hz, 2 H), 7.45 (d, J=8.1 Hz, 2 H), 4.03 (t, J=7.2 Hz, 2 H), 2.96 (s, 3 H), 2.38 (s, 3 H), 1.75 (t, J=7.2 Hz, 2 H), 1.01 (s, 6 H); MS (ESI) m/z: 295.0 (M+Na+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[CH2:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])=[C:12]([O:28][CH3:29])[CH:11]=1)[CH3:9]>C1COCC1>[CH2:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])(=[O:23])=[O:22])=[CH:17][C:16]=2[F:25])=[C:12]([O:28][CH3:29])[CH:11]=1)[CH3:9]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OC)c1
Reactant: CC(=O)NCCN
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCNC(C)=O)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
N-Acetylethylenediamine (1.1 mmol; 0.10 mL) was slowly added to a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (0.94 mmol; 325 mg) and TEA (2.8 mmol; 0.40 mL) in anhydrous THF (5 mL), under argon at 0° C. The reaction was stirred overnight with progressive warming to room temperature. Concentrated, the mixture was purified by chromatography (dichloromethane/methanol/ammonia gradient) to yield the title compound as a yellow oil (142 mg; 0.35 mmol; 37%) used as such in the following reaction.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]1[C:9]([CH3:14])=[N:10][O:11][C:12]=1[CH3:13].[NH2:15][CH2:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=2)=[CH:20][CH:19]=1.[OH-].[Na+]>CN(C)C=O>[CH3:14][C:9]1[C:8]([CH2:7][NH:15][CH2:16][CH2:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][N:24]=3)=[CH:20][CH:19]=2)=[C:12]([CH3:13])[O:11][N:10]=1
Reactant: Cc1noc(C)c1CCl
Reactant: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CNCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
Add sodium bicarbonate (0.0481 g, 0.573 mmol) to a stirred solution of 4-(chloromethyl)-3,5-dimethylisoxazole (0.054 mL, 0.435 mmol), and 6-[4-(2-amino-ethyl)-phenoxy]-nicotinamide (0.1004 g, 0.390 mmol) in dimethylformamide (4 mL). Heat the reaction to reflux under nitrogen for 4 h. Cool to room temperature, pour the reaction mixture into 1 N sodium hydroxide (50 mL), extract with diethyl ether (3× 50 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 0.8% concentrated ammonium hydroxide/8% ethanol/chloroform to yield 0.0843 g (59%) of 6-(4-{2-[(3,5-dimethyl-isoxazol-4-ylmethyl)-amino]-ethyl}-phenoxy)-nicotinamide: mass spectrum (ion spray): m/z 367.1 (M+1); 1H NMR (CDCl3): 8.57 (dd, 1H), 8.16 (dd, 1H), 7.26-7.22 (m, 4H), 7.09-7.05 (m, 2H), 6.96 (d, 1H), 3.54 (s, 2H), 2.88-2.79 (m, 4H), 2.33 (s, 3H), 2.20 (s, 3H), 1.50 (br s, 1H).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1.CI.[NH4+]>O1CCCC1.O>[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]([CH3:1])([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)[C@H]1CCC[C@@H](OC)C1
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCC(OC)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a 2M-lithium diisopropylamide solution (7.32 ml, 0.0146 mmol) was added dropwise to a solution of methyl cis-3-methoxycyclohexane-carboxylate (1.80 g, 0.0105 mol) in tetrahydrofuran (36 ml) at −78° C. over a period of 15 minutes. After 3 hours, a solution of methyl iodide (4.45 g, 0.0314 mmol) in tetrahydrofuran (9 ml) was added dropwise thereto over a period of 20 minutes, and the resulting mixture was slowly warmed up to 0° C. After 3 hours, a saturated aqueous ammonium solution was added thereto and the resulting mixture was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain methyl 3-methoxy-1-methylcyclohexanecarboxylate (1.8985 g, 98%, a 4:1 mixture of isomers).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>CCOCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2
Reactant: Cc1ccccc1[Mg]Br
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1cccc2c1C=C(C(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-isopropylindene (9.8 g, 51 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) are dissolved in 150 mL of Et2O. 2-Methylphenylmagnesium bromide (51 mmol) as an Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq) and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 6.6 g (52%).
Reaction SMILES: C(OC(N1CC[CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16]C2C1)=O)(C)(C)C.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32].C([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])C>>[CH2:31]([NH:33][C:34](=[O:35])[O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([S:21]([C:18]2[CH:19]=[CH:20][C:14]3[CH:11]4[CH2:40][CH2:39][NH:38][CH2:41][CH:42]4[O:16][C:15]=3[CH:17]=2)(=[O:22])=[O:23])[CH:25]=1)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cccc(O)c4)cc3OC2C1
Reactant: CCN(CC)CC
Reactant: CCN=C=O
Product: CCNC(=O)Oc1cccc(S(=O)(=O)c2ccc3c(c2)OC2CNCCC32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(3-hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzofuro[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (30 mg, 0.07 mmol), ethyl isocyanate (0.5 ml, excess) and triethylamine (0.5 mL, excess) was stirred at r.t. After 18 h, the mixture was filtered, and the filtrate evaporated. Purification by preparative TLC (hexane:EtOAc 40:60) followed by removal of N-Boc protecting group with 4N HCl using a general procedure afforded the title product. mp 217-219° C., MS m/z 403 [M+H]+. 1H-NMR (400 MHz, DMSOd6): δ 8.97 (br s, 1H), 7.80 (d, J=7.96 Hz, 1H), 7.62 (s, 1H), 7.60-7.55 (m, 3H), 7.43 (overlapping s and d, 2H), 4.95 (m, 1H), 3.57 (m, 2H), 3.44 (m, 1H), 3.14 (m, 2H), 2.94 (m; 2H), 2.55 (s, 2H), 2.12 (m, 1H), 1.52 (m, 1H), 1.09 (t, 3H).
Reaction SMILES: O[N:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:7])[O:4][CH2:5][CH3:6].[OH-:14].[K+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>C(O)C>[CH2:5]([O:4][C:3]([NH:2][C:8]1[CH:13]=[CH:12][C:11]([C:20]2[N:21]=[CH:22][C:17](=[O:14])[NH:18][CH:19]=2)=[CH:10][CH:9]=1)=[O:7])[CH3:6]
Reactant: CCOC(=O)N(O)c1ccccc1
Reactant: Clc1cnccn1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
Ethyl N-hydroxy-N-phenylcarbamate (7.9 g) was added to a solution of potassium hydroxide (2.45 g) in ethanol (125 ml). After the solution had been stirred for 30 minutes, chloropyrazine (5 g) and a small amount of molecular sieve (4A) pellets were added. The solution was stirred for two hours and allowed to stand for 144 hours to give a dark brown solution. This solution was evaporated under reduced pressure to give an oil which was washed with dilute acetic acid and solidified. This solid was recrystallised from n-propanol, stirred with water for two hours to remove salts, collected and dried to afford the title compound (1.8 g), m.p. 260°-262° C.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[CH2:34][OH:35])=[C:17]([O:36][CH3:37])[CH:16]=1.O>C(Cl)Cl>[C:4]([Si:1]([O:35][CH2:34][C:25]1[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=1[C:18]1[CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]([F:14])=[CH:16][C:17]=1[O:36][CH3:37])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyldimethylsilyl chloride (0.48 g, 3.21 mmol) and imidazole (0.50 g, 7.30 mmol) were added successively to a stirred solution of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (1.00 g, 2.93 mmol) in dry CH2Cl2 (13.4 mL) at room temperature under N2 and the reaction was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 1% EtOAc in hexanes) to afford tert-butyl{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane as a colorless oil. Rf=0.16 (1% EtOAc in hexanes). LCMS calc.=457.2; found=457.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.69 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H), 3.29-3.21 (m, 1H), 1.28 (d, J=6.9 Hz, 6H), 0.93 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: Cl[Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Cl:9][C:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[CH:11]=1>CN(C)P(=O)(N(C)C)N(C)C.O>[Cl:9][C:10]1[C@@H:14]([O:15][Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:13][C:12](=[O:16])[CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1C=C(Cl)[C@@H](O)C1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC(=O)C=C1Cl
Reaction time: 20 h
Yield: 99.1 %

Procedure:
Chlorodimethyl-t-butylsilane (485 mg, 3.22 mmol) was added over 5 min to the crude (4S)-enone (7) (247 mg) in hexamethylphosphoric triamide (2 ml) at 0°. After stirring at 4° for 20 h the solution was diluted with water (10 ml) and extracted with ether (3×10 ml). The combined ether extracts were washed with water (3×10 ml), dried (MgSO4) and evaporated to give a pale yellow oil (456 mg) which was chromatographed on a column of silica gel (25 g) with methylene dichloride-methanol (50:1) as eluant. The (4S)-enone (8; R1 =Me2ButSi) [243 mg, 61% from the 3,5,5-trichloro-4-hydroxycyclopent-2-en-1-one (6)] was obtained as a colourless oil, [α]35225 +1050° (c. 9.14×10-2, hexane), [α]23425 -16,140° (c 1.83×10-3, hexane), [θ]33325 +6700° (c 9.14×10-2, hexane), [θ]22225 -80,330° (c 1.83 ×10-3, hexanel). (Found: C, 53.65; H, 7.95; Cl, 14.6. C11H19ClO2Si requires C, 53.55; H, 7.75; Cl, 14.35%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.CN(C=[O:25])C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[O:25])[N:15]=1
Reactant: CN(C)C=O
Reactant: Cc1cccc(F)n1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: O=Cc1cccc(F)n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (6.54 mL, 1.2 equiv) in 30 mL of THF at 0° C., a solution of n-butyllithium (17.1 mL, 2.5M in hexanes) is added dropwise. Stirring is continued for 15 minutes at 0° C., the reaction is then cooled to −78° C. 2-Fluoro-6-methylpyridine (4.00 mL, 38.9 mmol) is added dropwise to the cold solution. The reaction mixture is stirred at −78° C. for 1 hours and then quenched with DMF (4.52 mL, 1.5 equiv). The reaction is maintained at −78° C. for 30 minutes and then warmed to 0° C. The cold solution is added to a mixture of sodium periodate (24.9 g) in 120 mL of water at 0° C. The reaction mixture is allowed to gradually warm to room temperature over 1 hours and then stirred at room temperature for 24 hours. The reaction mixture is filtered through a plug of celite to remove the precipitate and the plug is washed with ether. The organic layer is separated, washed with aqueous sodium bicarbonate (1×40 mL), then with 0.25M KH2PO4 (1×40 mL) and then brine (1×40 mL). The organic solution is dried (NaSO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18](Br)=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4].O>CS(C)=O>[C:3]([O:6][C@H:7]([CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][O:24][CH2:25][CH3:26])[C:18]([NH:2][CH3:1])=[N:17][C:16]=2[N:15]([CH3:28])[C:13]1=[O:14])(=[O:5])[CH3:4]
Reactant: CN
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Solvent: CS(C)=O
Solvent: O
Product: CCOCn1c(NC)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 70 °C

Procedure:
A 40% aqueous solution of methylamine (10 ml) was added to a solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (0.450 g) in dimethylsulfoxide (20 ml). After heating at 70° C. for 6 hours, the mixture was treated with water (50 ml) and extracted with ethyl acetate (3x 50 ml). The combined extracts were washed with water (2x 30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol-ethyl acetate to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-3-methyl-8-methylaminoxanthine (0.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].O[Li].O>C1COCC1.CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][CH:17]=[CH:16]3)=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)ccc1-c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a stirring solution of ethyl 5-chloro-2-(quinolin-6-yl)benzoate (0.244 g, 0.78 mmol) in 1:1:1 THF/EtOH/H2O (21 ml) at RT was added LiOH—H2O (0.164 g, 3.91 mmol). The resulting reaction mixture was stirred at RT overnight. Solvent was removed under reduced pressure and the residue was diluted with H2O (10 mL). The aqueous solution was acidified to pH˜4 with 3M HCl and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated to afford 5-chloro-2-(quinolin-6-yl)benzoic acid (0.201 g, 91% yield) as a white solid. MS (ESI) m/z: 284.0 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([O:25]CC)=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.O>[CH:1]1([C:4]2[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7](=[O:22])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(F)cc3)ccn2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 60 °C

Procedure:
A solution of ethyl 1-cyclopropyl-8-(4-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.329 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 44 as a yellow solid (110 mg, 99%). ESI-MS m/z: 338 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.37 (d, J=7.5 Hz, 1H), 8.30 (s, 1H), 7.70-7.61 (m, 3H), 7.51-7.45 (m, 2H), 2.89 (s, 3H), 2.53-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.82 (m, 2H).